KR100768034B1 - Pharmaceutical composition - Google Patents

Abstract

The present invention relates to a granular pharmaceutical composition containing a drug having an unpleasant taste, a waxy substance and a sugar alcohol, a preparation method thereof, and an oral pharmaceutical formulation combining the granular composition thereof. This formulation is excellent in the masking property of the unpleasant taste of a drug, a good feeling of taking, and it can be taken easily also in an elderly person, a child, and a patient who is difficult to swallow. It is also suitable for landscape administration.

Description

Pharmaceutical composition {PHARMACEUTICAL COMPOSITION}

The present invention relates to a granular pharmaceutical composition which masks an unpleasant taste of a drug and has a good feeling of taking, and a preparation using the same.

When the orally administered formulation has an unpleasant taste, it causes a decrease in use of the doser and often fails to obtain the expected therapeutic effect.

As a method of masking the unpleasant taste regarding a fine granule, the spray coating method using a water-insoluble polymer, the method of adding microencapsulation, or a sweetening agent are known. Regarding the spray coating method using a water-insoluble polymer, Japanese Patent Publication No. 30709/1987 discloses a persistent agent for coating a nucleus containing a drug with ethyl cellulose, and the thickness of the ethyl cellulose coating film is disclosed. It is described that by changing the rate of release of the drug can be controlled. However, this is a technique for long-acting formulations and not a technique used for immediate release formulations that combines an unpleasant taste masking property. In addition, the coating using water-insoluble polymer has a foreign body feeling when it is put into the mouth, and when taken into the inner tooth, there is a problem in taking dose such as pain. On the other hand, the method using the microcapsules has a drawback that the manufacturing method is complicated by using an organic solvent, the yield is low, and the manufacturing cost is high. In addition, the method by the addition of a sweetening agent does not have enough masking effect against a drug with a strong unpleasant taste.

In addition, Japanese Patent Application Laid-Open No. 242568/1995 discloses spray granulation of this solution after dissolving or suspending drugs and channeling agents exhibiting an unpleasant taste by heating and dissolving hydrophobic substances and surfactants having a melting point of 45 to 90 ° C. The granular agent obtained by this is disclosed. The purpose of adding the surfactant and the hydrophobic agent is to speed up the elution of the drug and is contained 5 to 35% in the composition, respectively. However, it is preferable that the amount of the surfactant used is small from the viewpoint of safety. Furthermore, in consideration of the processing of the formulation after spray granulation, it is preferable to reduce the amount of additives used during spray granulation so that many other additives can be used in the formulation processing after spray granulation. Therefore, it is advantageous not to use surfactants and hydrophobic agents as much as possible. Japanese Patent Application Laid-Open No. 267850/1995 discloses a waxy substance which is mixed, heated and melted with one or several unpleasant tastes, one or several water-soluble polymers, and one or several waxy substances. And a pharmaceutical composition obtained by granulating together with a water-soluble polymer. The purpose of adding a water-soluble polymer is to speed up the elution of the drug in the same manner as described above, and 5 to 60% is blended in the composition. However, it is preferable not to use the water-soluble polymer for the same reason as described above, or to use as little as possible.

In addition, as a satisfactory quality of the solid granular material, in particular, the powder, in addition to the unpleasant taste masking property described above, good landscape-permeability can be mentioned. Cervical administration is mainly administered to those who can't swallow the preparation. Dispersing the powder in water and transferring it to a syringe is injected into a tube inserted into the digestive tract through the patient's nose or abdomen. . Since administration is prepared at the time of use of the dispersion, the powder is required to be uniformly dispersed in a short time and not to be blocked in the syringe and the tube. However, powders coated with pH-dependent polymers, such as methacrylic acid copolymers, aggregate in non-electrolyte solutions such as purified water or glucose solutions to block the syringes and tubes, so such powders are not suitable for administration of the landscape. In addition, an acid using a sugar such as lactose as an excipient is not suitable for landscape administration because clogging occurs in a syringe or a tube.

Accordingly, it is an object of the present invention to provide a granular pharmaceutical composition which is excellent in masking property of an unpleasant taste possessed by a drug, has a good feeling of taking, and can be administered in a landscape, and a preparation using the same.

The present inventors prepared granular materials containing drugs having an unpleasant taste and examined their performance in various ways. As a result, when a sugar alcohol is added to a combination of a drug having a unpleasant taste and a waxy substance, the present inventors have a surprisingly unpleasant taste. It was found that a pharmaceutical preparation having excellent masking effect and good taking feeling was obtained, and completed the present invention. In addition, the medicinal product was found to be administered in the landscape.

That is, the present invention provides a granular pharmaceutical composition containing an unpleasant taste, a waxy substance and a sugar alcohol, a preparation method thereof, and an oral pharmaceutical preparation containing the granular pharmaceutical composition.

Best Mode for Carrying Out the Invention

In the present invention, the unpleasant taste also includes bitterness, astringent taste, pungent taste, irritation, and unpleasant odor when the user puts the drug in his mouth.

In the present invention, the drug having an unpleasant taste exhibits the above unpleasant taste and is not particularly limited as long as it is a drug used as a medicine. For example, hydrochloric acid setlaxate, ecapapid, nepyracetam, talampicillin hydrochloride, indenolol hydrochloride, hydrazine hydrochloride, chloropromazine hydrochloride, tiaramid hydrochloride, berberine hydrochloride, digitoxin, sulfiraline, hydrochloric acid Azelastine, ethyllephrine hydrochloride, diltiazem hydrochloride, propranolol hydrochloride, chloramphenicol, aminophylline, erythromycin, clarithromycin, phenobarbital, calcium pantothenate, indeloxazine hydrochloride, aminoguanidine hydrochloride, bifemelan hydrochloride, 7β- [2- (2-Aminothiazol-4-yl) -2- (Z) -hydroxyiminoacetamido] -3-N, N-dimethylcarbamoyloxymethyl-3-cepem-carboxylic acid -1- (isopropoxycarbonyloxy) ethyl ester hydrochloride, (E) -3- (2-methoxy-3,6-dimethyl-1,4-benzoquinone-5-yl) -2- [5- (3-pyridyl) pentyl] -2-propenoic acid, aminophylline, theophylline, diphenhydramine, metoclopramide, phenylbutazone, phenobarbital, ampicillin, cime Thymidine, pamotidine, nizatidine, acetaminophen, epipyrazole, pyrazineamide, caffeine, ethionamide, carvedilol, ranitidine hydrochloride, roxatidine hydrochloride, imipraamine hydrochloride, ephedrine hydrochloride, diphenhydramine hydrochloride , Donepedil hydrochloride, tetracycline hydrochloride, doxycycline hydrochloride, napazoline hydrochloride, noscapine hydrochloride, papaverine hydrochloride, dextromethorphan hydrobromide, thimepidium bromide, chlorphenylamine maleic acid, alimethazine hydrochloride Need, N-methylscopolamine methyl sulfate, maleic acid cinefazide, arginine hydrochloride, histidine hydrochloride, lysine hydrochloride, lysine acetate; Coridalis Tuber, Phellodendron Bark, Coptis Rhizome, Nux Vomica, Ephedra Herb, Ipecac, Scopolia Herbal medicines such as (Scopolia Rhizome), Belladonna or Sophora Root, or extracts of the herbal medicines; General Formulas (1) to (4) below

(Wherein R ^1a , R ^1b and R ^1c are each independently a linear or branched alkyl group having 1 to 6 carbon atoms which may have a substituent, a cyclic alkyl group having 3 to 6 carbon atoms which may have a substituent, or a substituent) It means the aryl group which may have, or the heteroaryl group which may have a substituent.

R ^2a , R ^2b , R ^2c and R ^2d each independently represent a hydrogen atom or a linear or branched alkyl or amino group having 1 to 6 carbon atoms which may have a substituent; R ^3a , R ^3b , R ^3c and R ^3d each independently represent a hydrogen atom or a halogen atom; R ^4a or R ^4c is a hydrogen atom, a halogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms which may have a substituent or a linear or branched alkoxyl group having 1 to 6 carbon atoms which may have a substituent Means; R ^5a means a linear or branched alkyl group having 1 to 6 carbon atoms which may have a hydrogen atom or a substituent; Y ^a , Y ^b , Y ^c and Y ^d each independently represent a nitrogen-containing group). And the following general formula (5)

R ¹ -CH (R ² ) -R ³ (5)

[Wherein, R ¹ is an alkyl group having 1 to 4 carbon atoms, a halogen atom, an alkyl group having 1 to 4 carbon atoms substituted with fluorine, an alkoxy group having 1 to 4 carbon atoms, an alkoxyl group having 1 to 4 carbon atoms substituted with fluorine, a cyano group and a nitro group A phenyl group which may have 1 to 3 substituents selected from the group consisting of: R ² represents a hydrogen atom, a carboxyl group, an alkoxycarbonyl group having 1 to 6 carbon atoms or a halogen atom, a hydroxyl group, an alkoxyl group having 1 to 4 carbon atoms, or a cyano group which may be substituted with an aliphatic acyl group having 1 to 7 carbon atoms; And R ³ is an alkoxyl group having 1 to 4 carbon atoms substituted with a hydroxyl group, an alkoxyl group having 1 to 4 carbon atoms, an alkoxyl group having 1 to 4 carbon atoms or an alkanoyloxy group having 1 to 6 carbon atoms, and an aralkyl having 7 to 14 carbon atoms. An oxy group, a C1-C18 alkanoyloxy group, a C3-C7 cycloalkylcarbonyloxy group, a C6-C10 arylcarbonyloxy group, a C1-C4 alkoxycarbonyloxy group, or C7-C7 A 4,5,6,7-tetrahydrothieno [3,2-c] pyridin-5-yl group, which may be substituted with a 14 aralkyloxycarbonyloxy group.]

And a drug selected from 4,5,6,7-tetrahydrothieno [3,2-c] pyridines or salts thereof.

The pyridonecarboxylic acid compounds represented by the above general formulas (1) to (4) and salts thereof and methods for producing the same are disclosed in Japanese Patent Laid-Open Nos. 53-141286, 55-31042, 57-46986, and 57- 77683, 60-36482, 60-64979, 60-228479, 62-252772, 62-252790, 62-277362, 1-230558, 1-258666. 1-294680, 2-28178, 2-124873, 2-231475, 5-271229, 7-309864, 8-41050 and WO 91/02526, WO 94/14794, WO 94/15933, WO 95/5373, WO 96/37475, WO 96/39407, WO 97/29102, WO 97/19072, WO 97/40037, WO 98/02431, WO 98/13370, WO 98/18783, WO 98/24781, WO 98/52939, WO 98/54169, and WO 98/58923, and the like, which also discloses a manufacturing method. In addition, the compound represented by General formula (5), and its salt are described in Unexamined-Japanese-Patent No. 50-46688, Japan Unexamined-Japanese-Patent No. 58-10583, 59-27895, 6-41139, etc. It can manufacture by the method which there is.

The compounds represented by the general formulas (1) to (5) may have asymmetric carbons, and optical or diastereomers may be present. The isomers in pure form, any mixtures of these isomers, racemates and the like are all included in the present invention. Moreover, the compound represented by the said General formula (1)-(5) or its salt may exist as a hydrate and a solvate, and this is also included in this invention.

In the present invention, the drug having an unpleasant taste is preferably poorly soluble in the waxy substance in view of the masking effect, more preferably water soluble and poorly soluble in the waxy substance.

Moreover, the following compound or its salt is mentioned as a preferable example among the compound or its salt represented by said General Formula (1)-(4).

Moreover, the following are mentioned as a preferable example among the compound represented by the said General formula (5), or its salt.

2-hydroxy-5- (α-cyclopropylcarbonyl-2-chlorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine,

2-hydroxy-5- (α-propionyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine,

2-hydroxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine,

2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine,

2-propionyloxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine,

2-butyryloxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine,

2-pivaloyloxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine,

2-valeryloxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine,

2-hexanoyloxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine,

2-t-butoxycarbonyloxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine,

2-pivaloyloxymethoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine,

5- (α-cyclopropylcarbonyl-2-chlorobenzyl) -2-oxo-2,4,5,6,7,7a-hexahydrothieno [3,2-c] pyridine,

5- (α-propionyl-2-fluorobenzyl) -2-oxo-2,4,5,6,7,7a-hexahydrothieno [3,2-c] pyridine,

5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -2-oxo-2,4,5,6,7,7a-hexahydrothieno [3,2-c] pyridine,

2-acetoxy-5- (α-cyclopropylcarbonyl-2-chlorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine,

2-hydroxy-5- (α-2-fluorocyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine,

5- (α-2-fluorocyclopropylcarbonyl-2-fluorobenzyl) -2-oxo-2,4,5,6,7,7a-hexahydrothieno [3,2-c] pyridine,

2-acetoxy-5- (α-2-fluorocyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine,

5- (α-methoxycarbonyl-2-chlorobenzyl) -2-oxo-2,4,5,6,7,7a-hexahydrothieno [3,2-c] pyridine,

2-acetoxy-5- (α-methoxycarbonyl-2-chlorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine,

5- (α-methoxycarbonyl-2-fluorobenzyl) -2-oxo-2,4,5,6,7,7a-hexahydrothieno [3,2-c] pyridine,

2-acetoxy-5- (α-methoxycarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine,

5- (2-chlorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine (common name: ticlopidine; available as hydrochloric acid ticlopidine),

5- (α-methoxycarbonyl-2-chlorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine (common name: clopidogrel; available as clopidogrel sulfate),

5- (α-methoxycarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine,

5- (α-cyclopropylcarbonyl-2-chlorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine,

5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine,

5- (α-propionyl-2-chlorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine and

5- (α-propionyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine and salts thereof.

In the present invention, as the drug having an unpleasant taste, among those, offroxacin, levoproxacin, citaproxacin hydrate, hydroxetase lactate, nepyracetam, hydrochloric acid ticlopidine and clopidogrel are preferable.

In the present invention, examples of the waxy material (specifically, melting point of 40 to 150 ° C) include hardened oil (e.g. hardened castor oil, hardened soybean oil, hardened rapeseed oil, hardened cottonseed oil), animal and vegetable fats and oils (e.g. carnauba wax, Oils and fats such as pewter, beeswax and tallow); Alcohols and polyhydric alcohols such as higher alcohols (eg stearyl alcohol, cetanol) and polyethylene glycols (eg macrogol 4000, macrogol 6000); Fatty acids and derivatives thereof such as higher fatty acids (eg stearic acid, palmitic acid) and glycerin fatty acid esters and sucrose fatty acid esters (eg monofatty acid glycerin esters, trifatty acid glycerin esters); Or mixtures of two or more of these substances. Among these, curing oils, fatty acids and derivatives of fatty acids are preferable, curing oils, higher fatty acids and fatty acid esters are more preferable, and curing oils, monofatty acid glycerine esters, trifatty acid glycerine esters and stearic acid are particularly preferable. Further, in view of the masking effect of the unpleasant taste of the drug, the melting point of the waxy substance is preferably lower than the melting point of the drug.

In the present invention, the sugar alcohol preferably has a low heat of dissolution, for example, erythritol, xylitol, sorbitol, maltitol or a mixture of two or more thereof. From the point of view of taking a dose, sugar alcohols having a heat of dissolution of -30 cal / g or less are preferable, and erythritol and xylitol are particularly preferable.

In the present invention, the weight ratio of the drug to the unpleasant taste and the waxy substance is preferably 1: 1 to 1: 5, more preferably 1: 2 to 1 :: from the viewpoint of the masking effect of the unpleasant taste and the elution balance. It is in the range of 3. In addition, the blending amount of the sugar alcohol is preferably 10% by weight or more, more preferably 10 to 99.9% by weight, more preferably 20 to 80% by weight in the granular composition from the viewpoint of an unpleasant taste masking effect, elution property and feeling of taking. It is preferable and 30 to 70 weight% is especially preferable.

The granular pharmaceutical composition of the present invention is obtained by heating and melting a waxy substance, dispersing or dissolving a drug having an unpleasant taste therein, and then granulating the granules first by using a dispersion or a solution. It is manufactured by mixing or secondary granulation of the obtained granulated material and sugar alcohol.

Here, as the primary granulation means, spray granulation, melt granulation, and the dispersion or the solution may be pulverized after cooling, solidifying, but spray granulation is preferable. The spray-chilling method and the spray-drying method are preferable because they can be easily obtained as fine particles having a particle size such that they do not feel foreign matter such as stickiness even when the granulated material is placed on the tongue. As particle size, the range of 50-200 micrometers, especially 80-120 micrometers is preferable.

Here, when spray granulation is employed as the primary granulating means, a small amount of surfactant may be added for the purpose of reducing the adherence of the granules to the inner wall of the manufacturing machine in the spray chilling step. The amount of the surfactant added is preferably about 0.5 to 5% by weight, particularly about 1 to 4% by weight, based on the primary granulated product.

As a means for the second granulation of the granulated product and the sugar alcohol obtained by the first granulation, a wet fluidized bed granulation method using a binder solution such as hydroxypropyl cellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyethylene glycol, monostearic acid The melt granulation method using a low melting point substance, such as glycerin, as a binder is mentioned.

It is preferable that the granular pharmaceutical composition of this invention is obtained by the method of secondary granulation of the granular material obtained by primary granulation and sugar alcohol. That is, in the mouth, since the sugar alcohol used for secondary granulation dissolves for about 10 seconds by saliva, only the waxy substance particles in which the drug obtained by primary granulation is dispersed remain, but the waxy substance particles are fine spheres. Because it does not feel foreign object. In addition, since the drug is uniformly dispersed in the waxy material to form particles, so that the dissolution of the waxy material in the mouth is very small, the unpleasant taste of the drug is well masked. In addition, sugar alcohols, especially erythritol and xylitol, sweeten when put into the mouth and have a refreshing feel, thus contributing to masking the unpleasant taste of the drug. After the waxy substance particles are swallowed, they release the drug in the digestive tract and the released drug is absorbed in vivo.

The granular pharmaceutical composition of the present invention may be used as it is or as needed, or other additives may be formulated into oral pharmaceutical preparations such as powders, granules, dry syrups, tablets and capsules. Among these, powder, granule, and dry syrup are preferable.

 Other additives used herein include binders such as polyvinylpyrrolidone, polyvinyl alcohol, hydroxypropyl cellulose, hydroxypropylmethylcellulose, methyl cellulose, polyethylene glycol, and monostearate glycerin; Sweetening agents such as aspartame, saccharin sodium, saccharin, somartin and stevia; Fragrances such as X-menthol and 1-menthol; Fluidizing agents such as hard silicic anhydride, magnesium metasilicate aluminate, talc, synthetic aluminum silicate, and ethyl cellulose; Disintegrating agents such as croscarmellose calcium, starch calcium gluconate, low-substituted hydroxypropyl cellulose; PH adjusters, such as sodium citrate and sodium hydrogencarbonate, etc. are mentioned. Although the water-soluble polymer is contained in the additive of this invention, it is preferable that it is 0.1 to 5 weight%, especially 1 to 4 weight% in a small amount in a formulation.

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto.

Example 1

200 parts by weight of glycerin monostearate was melted at about 90 ° C., and 100 parts by weight of levoproxacin was uniformly dispersed therein. This dispersion was spray cooled using a spray dryer to obtain a fine granulated product. 630 parts by weight of erythritol is added to 300 parts by weight of the granulated material, mixed by using a fluidized bed granulator, and then, 10 parts by weight of a polyvinyl alcohol solution of 10 W / V% of an aqueous solution of polyvinyl alcohol is sprayed on the mixture and flowed. Assembled. After completion of spraying, the mixture was subsequently dried in a fluidized bed granulator to obtain a granulated product. The powder which passed the sieve was obtained using this 30 granulated body (mesh size: 500 micrometers).

Example 2

197 parts by weight of glycerin monostearate was melted at about 90 ° C., and 3 parts by weight of polyoxyethylene (20) sorbitan monooleate (polysorbate 80) was mixed thereto. Further, 100 parts by weight of levoproxacin was uniformly dispersed in this mixed solution. This dispersion was spray cooled using a spray dryer to obtain a fine granulated product. 630 parts by weight of erythritol was added to 300 parts by weight of the granulated material, mixed with a fluidized bed granulator, and then 20 parts by weight of a polyvinyl alcohol solution of 10 W / V% of polyvinyl alcohol was sprayed onto the mixture to flow. Assembled. After completion of spraying, the granules were dried by drying in a fluidized bed granulator. The powder was passed through a sieve using No. 30 sieve (sieve size: 500 µm).

In the same manner as in Examples 1 and 2, powders using offroxacin, citaproxacin hydrate, hydroxetase lactate or nepyracetam as drugs were prepared, respectively.

Test Example 1 (Unpleasant taste masking evaluation: sensory test 1)

The sensory test was done about 940 mg of powder obtained in Example 1, and 950 mg of powder obtained in Example 2. When the amount of levoproxacin 100 mg equivalent powder was actually put into the mouth, the taste and the feeling of taking were evaluated. Both powders have been found to mask the very strong unpleasant taste of the drug for more than 30 seconds. In addition, even after 10 seconds after taking, there was no feeling of foreign body in the mouth.                 

Test Example 2 (Unpleasant taste masking evaluation: dissolution test 1)

An unpleasant taste masking test was done for 940 mg of the powder obtained in Example 1 and 950 mg of the powder obtained in Example 2. The unpleasant taste masking test was performed using the elution test apparatus at 500 ml of purified water as a test liquid, at a test liquid temperature of 37 ° C., a paddle method, and a rotation speed of 100 rpm. Drug alone was used as a control. The results (elution rate (%)) are shown in Table 1. Initial dissolution of the drug in the powder was markedly inhibited compared to the drug alone.

Dissolution test result Time in seconds 10 20 30 40 Drug alone 58 83 93 103 Example 1 2 6 12 29 Example 2 5 12 19 40

Test Example 3 (Landscape Administration Evaluation 1)

The landscape aptitude was evaluated for the powders obtained in Examples 1 and 2. Each of 950 mg was dispersed in 20 ml of purified water. This dispersion was transferred to a disposable syringe, and an enteral nutrient replenishment tube (tube name: ARGAIL, manufactured by Sharwood, Japan) was connected to a 1.0 mm inner diameter. The dispersion was extruded from the syringe and the blockage of the syringe tip and tube tip was evaluated.

The results are shown in Table 2.

Cervical administration aptitude evaluation result result Example 1 Clogging of the syringe tip and tube tip was not observed at all. Example 2 Clogging of the syringe tip and tube tip was not observed at all.

In the powders obtained in Examples 1 and 2, it was confirmed that clogging did not occur and smooth administration was possible.

Test Example 4 (Dissolution Test 1)

An elution test was performed on 940 mg of the powder obtained in Example 1 and 950 mg of the powder obtained in Example 2. The dissolution test was carried out using a dissolution test apparatus and 900 ml of the 13th revised Japanese Pharmacopoeia Disintegration Test No. 1 test solution, at a test solution temperature of 37 ° C., a paddle method, and a rotation speed of 50 rpm. As a result, as shown in Table 3, it was observed that the powder shows good elution.

Dissolution test result time 5 minutes later 10 minutes later 20 minutes later 30 minutes later 45 minutes later 60 minutes later Example 1 100 100 100 100 100 100 Example 2 98 98 98 98 98 98

(Average Dissolution Rate (%))

Example 3

216 parts by weight of tri fatty acid glycerin ester was melted at about 80 ° C., and 11.2 parts by weight of polyoxyethylene (20) sorbitan monooleate (polysorbate 80) was mixed thereto. Further, 97.8 parts by weight of clopidogrel sulfate was uniformly dispersed in this mixed solution. This dispersion was spray cooled using a spray dryer to obtain a fine granulated material. 169 parts by weight of erythritol and 5 parts by weight of aspartame were added to 325 parts of the granulated product to obtain a powder.

Example 4

216 parts by weight of tri fatty acid glycerin ester was melted at about 80 ° C., and 11.2 parts by weight of polyoxyethylene (20) sorbitan monooleate (polysorbate 80) was mixed thereto. Further, 97.8 parts by weight of clopidogrel sulfate was uniformly dispersed in this mixed solution. This dispersion was spray cooled using a spray dryer to obtain a fine granulated material. 169 parts by weight of erythritol is added to 325 parts of the granulated material, mixed by using a fluidized bed granulator, and then sprayed into the mixture by a solution of 10 parts by weight of 10 V /% of polyvinyl alcohol as a polyvinyl alcohol. Flow assembled. After spray termination, the granules were dried by drying in a fluid bed granulator. 514 parts by weight of this granulated material and 5 parts by weight of aspartame were mixed to obtain a powder.

Example 5

216 parts by weight of trifatty acid glycerin ester was dissolved in dichloromethane. 97.8 parts by weight of clopidogrel sulfate and 32.6 parts by weight of ethyl cellulose were uniformly added thereto. This dispersion was spray cooled using a spray dryer to obtain a fine granulated material. 147.6 parts by weight of erythritol and 5 parts by weight of aspartame were added to 346.4 parts by weight of the granulated product to obtain a powder.                 

Example 6

216 parts by weight of trifatty acid glycerin ester was dissolved in dichloromethane. Again, 97.8 parts by weight of clopidogrel sulfate and 32.6 parts by weight of ethyl cellulose were uniformly dispersed therein. This dispersion was spray cooled using a spray dryer to obtain a fine granulated product. 147.6 parts by weight of erythritol is added to 346.4 parts by weight of the granulated material, mixed by using a fluidized bed granulator, and then 20 parts by weight of a polyvinyl alcohol solution of 10 W / V% of polyvinyl alcohol is sprayed onto the mixture and flowed. Assembled. After spray termination, a granulated product was dried in a fluidized bed granulator. 514 parts by weight of this granulated material and 5 parts by weight of aspartame were mixed to obtain a powder.

Comparative Example 1

135 parts by weight of trifatty acid glycerin ester was melted at about 80 ° C., and 7 parts by weight of polyoxyethylene (20) sorbitan monooleate (polysorbate 80) was mixed thereto. Again, 61 parts by weight of clopidogrel sulfate was uniformly dispersed in this mixed solution. This dispersion was spray cooled using a spray dryer to obtain a fine granulated product. 147.6 parts by weight of lactose and 5 parts by weight of aspartame were added to 346.4 parts by weight of the granulated product to obtain a powder.

5 on the test (Unpleasant taste masking evaluation: sensory test 2)

The sensory test was done about 500 mg of powders obtained in Examples 3-6. When the amount of clopidogrel sulfate 100 mg equivalent powder was actually put into the mouth, the taste and the feeling of taking were evaluated. It was found that all powders masked the very strong unpleasant taste of the drug for at least 30 seconds. Also, after taking 10 seconds, no foreign body felt in the mouth.

 Test Example 6 (Unpleasant taste masking evaluation: dissolution test 2)

The unpleasant taste masking test was done with respect to 500 mg of powder obtained in Examples 3-6. The unpleasant taste masking test was carried out using a dissolution test apparatus, 300 ml of purified water as the test liquid, at a test liquid temperature of 37 ° C., a paddle method, and a rotational speed of 100 rpm. As a result, in all the Examples, it was confirmed that the initial dissolution of the powder of the drug was significantly suppressed compared to the drug alone.

Test Example 7 (Landscape Aptitude Evaluation 2)

The landscape aptitude was evaluated for the powders obtained in Comparative Examples 1 and 5. 500 mg each was dispersed in 20 ml of purified water. This dispersion was transferred to a disposable syringe, and an enteral nutrient replenishment tube (tube name: ARGAIL, manufactured by Sharwood, Japan) was connected to a 1.0 mm internal diameter. The dispersion was extruded from the syringe and the blockage of the syringe tip and tube tip was evaluated.

The results are shown in Table 4.

Cervical administration aptitude evaluation result result Comparative Example 1 Immediately after extrusion of the formulation, blockage occurred at the tip of the tube, so that the dispersion could hardly be extruded. Example 5 No clogging of powder was observed at the syringe tip and tube tip.

 The powder obtained in Comparative Example 1 was difficult to administer, and the aptitude for cervical administration could not be confirmed. On the contrary, it was confirmed that the powder obtained in Example 5 did not produce blockage and smooth administration was possible.

Test Example 8 (Dissolution test 2)

An elution test was carried out for 326.5 mg of the powder obtained in Example 3. The dissolution test was carried out using a dissolution test apparatus and 900 ml of the thirteenth revised Japanese Pharmacopoeia Disintegration Test No. 1 solution containing 1% of sodium lauryl sulfate as the test solution. The test solution temperature was 37 ° C., paddle method, and rotation speed 50 rpm. . As a result, as shown in Table 5, it was confirmed that the powder of Example 3 exhibited good elution.

Dissolution test result time 10 minutes later 15 minutes later 20 minutes later 30 minutes later 45 minutes later 60 minutes later Average dissolution rate 75.7% 83.4% 88.5% 94.0% 99.7% 100.9%

According to the present invention, it is possible to obtain a pharmaceutical preparation which is excellent in the masking property of the unpleasant taste possessed by the drug, and which can be easily taken by the elderly, children and patients who have difficulty in swallowing. This formulation is also suitable for cervical administration.

Claims (20)

Drugs with unpleasant taste, hardened castor oil, hardened soybean oil, hardened rapeseed oil, hardened cottonseed oil, carnauba wax, pewter, tallow, stearyl alcohol, cetanol, polyethylene glycol, stearic acid, palmitic acid, monofatty acid glycerin, trifatty acid glycerin And granular pharmaceutical composition which is prevented from flocculating in water containing one or two or more waxy substances selected from the group consisting of sucrose fatty acid esters and erythritol. The granular pharmaceutical composition according to claim 1, wherein the granular pharmaceutical composition containing the drug having an unpleasant taste and a waxy substance and the agglomeration in water containing erythritol are prevented. The granular pharmaceutical composition according to claim 1 or 2, wherein the drug having an unpleasant taste is a poorly soluble drug in a waxy substance. The granular pharmaceutical composition according to claim 1 or 2, wherein the drug having an unpleasant taste is water-soluble and poorly soluble in a waxy substance. The granular pharmaceutical composition according to claim 1 or 2, wherein the waxy substance is a waxy substance having a melting point of 40 to 150 占 폚. delete delete delete delete The drug with an unpleasant taste according to claim 1 or 2, wherein the drug having an unpleasant taste is hydrochloride setraxate, ecapapid, nepyracetam, talampicillin hydrochloride, indenolol hydrochloride, hydrazine hydrochloride, chlorpromazine hydrochloride, tiar hydrochloride Amides, berberine chloride, digitoxin, sulfinine, azelastine hydrochloride, ethyllephrine hydrochloride, diltiazem hydrochloride, propranolol, chloramphenicol, aminophylline, erythromycin, clarithromycin, phenobarbital, calcium pantothenate, indeloxin hydrochloride Photo, aminoguanidine hydrochloride, bifemelan hydrochloride, 7β- [2- (2-aminothiazol-4-yl) -2- (Z) -hydroxyiminoacetamido] -3-N, N-dimethylcar Bamoyloxymethyl-3-cepem-carboxylic acid-1- (isopropoxycarbonyloxy) ethyl ester hydrochloride, (E) -3- (2-methoxy-3,6-dimethyl-1, 4-benzoquinone- 5-yl) -2- [5- (3-pyridyl) pentyl] -2-propenoic acid, aminophylline, theophylline, diphenhydramine, metoclopramide , Phenylbutazone, phenobarbital, ampicillin, cimetidine, pamotidine, nizatidine, acetaminophen, epirisol, pyrazinamide, caffeine, ethionamide, carbenzirol, ranitidine hydrochloride, roxatidine hydrochloride, hydrochloric acid Imipraamine, Ephedrine hydrochloride, Diphenhydramine hydrochloride, Donepedyl hydrochloride, Tetracycline hydrochloride, Doxycycline hydrochloride, Napazoline hydrochloride, Noscapine hydrochloride, Papaverine hydrochloride, Dextromethorphan bromide, Thimepidium bromide, Maleic acid chlorine Phenylamine, tartaric acid amrimazine, hydrochloric acid hydrochloride, N-methylscopolamine methyl sulfate, maleic acid cinefazide, arginine hydrochloride, histidine hydrochloride, lysine hydrochloride, lysine acetate, clopidogrel, offoxacin, levoproxacin, Granular medicament prevented from flocculation in water, a drug selected from cytafloxacin hydrate and ticlopidine hydrochloride Composition. The granular pharmaceutical composition according to claim 1 or 2, wherein the drug having an unpleasant taste is offroxacin. The granular pharmaceutical composition according to claim 1 or 2, wherein the drug having an unpleasant taste is levoproxacin. The granular pharmaceutical composition according to claim 1 or 2, wherein the drug having an unpleasant taste is clopidogrel sulfate. The granular material according to claim 1 or 2, wherein the weight ratio of the drug having an unpleasant taste and the waxy substance is 1: 1 to 1: 5, and the content of sugar alcohol is 10% by weight or more in the composition. Medicinal composition. The method of claim 1 or 2, wherein the waxy substance is heated and melted, and after dispersing or dissolving a drug having an unpleasant taste therein, the granulated product obtained by primary granulation using this liquid and erythritol are mixed or A granular pharmaceutical composition in which aggregation is prevented in water obtained by secondary granulation. 16. The granular pharmaceutical composition according to claim 15, wherein the primary granulation is spray granulation. The granular pharmaceutical composition according to claim 15, wherein aggregation is prevented in water having a particle size of 50 to 200 µm of the primary granulated product. Consisting of hardened castor oil, hardened soybean oil, hardened rapeseed oil, hardened cottonseed oil, carnauba wax, pewter, tallow, stearyl alcohol, cetanol, polyethylene glycol, stearic acid, palmitic acid, monofatty acid glycerin, trifatty acid glycerin and sucrose fatty acid ester One or two or more wax-like substances selected from the group are heated and melted, and the dispersing or dissolving drug having an unpleasant taste is mixed therein. A method for producing a granular pharmaceutical composition, wherein the granular pharmaceutical composition is prevented from agglomeration in water, characterized by assembling. The granular pharmaceutical composition according to claim 1 or 2, which is used for oral use. 20. The granular pharmaceutical composition according to claim 19, wherein the formulation is a powder or granules.